8-ro-2-quinoline acrylic acid and lower alkyl esters thereof



S-RO-Z-QUINOLINE ACRYLIC ACID AND LOWER ALKYL ESTERS THEREOF Joseph G.Cannon, Madison, Wis., assignor to Wisconsin Alumni Research Foundation,Madison, Wis., a corporation of Wisconsin No Drawing. Filed Jan. 8,1960, Ser. No. 1,163 3 Claims. (Cl. 260-287) The present inventionrelates generally to derivatives of 8-hydroxy quinaldine and morespecifically to 8-RO2- quinoline acrylic acid and lower alkyl esters ofthe same, where R is selected from the group consisting of hydrogen andlower alkyl groups. The compounds are prepared by condensingS-hydroxyquinaldine or 8-lower alkoxyquinaldine with chloral, and thereaction of the resulting 'y,'y,'ytrichloro-u(8-hydroxyor loweralkoxy-Z-quinolyD-B-hydroxypropane with alcoholic potassium hydroxidewhich upon neutralization yields the desired S-RO-Z-quinoline acrylicacid.

The following examples will serve to illustrate the invention.

EXAMPLE I Ethers of 8-H ydroxyquinaldine Eleven grams (0.069 mole) of8-hydroxyquinaldine was dissolved in 50 ml. of absolute ethanol in a 250ml. standard-taper round-bottom flask equipped with a reflux condenserand a calcium chloride tube. To this solution was added 4 gm. (0.1 mole)of sodium hydroxide dissolved in 4 ml. of distilled water. To theresulting mass 0.1 mole of ethyl chloride was added, and the mixture wasrefluxed on a steam bath for live hours. The alcohol was then evaporatedon a steam bath at atmospheric pressure. The gummy residue was dissolvedin about 200 ml. of water and this solution was extracted several timeswith ether. The combined ethereal extracts were washed with a 100 ml.portion of 2.5% sodium hydroxide solution, and then with water. Theether extract was dried over anhydrous sodium sulfate, the ether wasremoved on a steam bath, and the oily residue was distilled underreduced pressure or crystallized. The ethyl ether has a melting point of52-53" C. In a similar manner the methyl and propyl ethers can bereadily prepared by use of the appropriate alkyl (methyl or propyl)halide.

EXAMPLE H Condensation of 8-Hydr0xyquinaldine and Its Ethers and ChloralTo 0.1 mole of 8hydroxyquinaldine or its ether contained in a 100 ml.standard-taper round-bottom flask equipped with a reflux condenser and acalcium chloride tube was added 15 ml. of pyridine (dried over potassiumhydroxide pellets) and 0.1 mole of chloral, and the mixture was heatedon a steam bath for two hours. The resulting tarry reaction mixture waspoured into about 250 ml. of ether, the ethereal solution was filtered,and the ether was removed on a steam bath. An excess of 1:6 hydrochloricacid was added to the residue and the resulting solution was heated toboiling. It was then filtered to remove tars, and the filtrate wascooled. On neutralizing the filtrate with solid sodium carbonate,'y,'y,'y-trichloro-u- (B-hydroxyor alkoxy-2-quinolyl)-/3-hydroxypropaneprecipitated from solution and was recrystallized from etha nol. TheS-hydroxy trichloro hydroxypropane derivative melts at ll3-114 C., andthe corresponding methyl, ethyl and propyl ethers (8-alkoxy derivatives)melt, respectively, at 127-128 C., 146-147 C., and 100-101 C.

3,056,700 Patented Oct. 2, 1952 EXAMPLE In S-Hydroxy-Z-Quinoline AcrylicAcid Twenty-five hundredths of a mole of potassium hydrox ide wasdissolved in ml. of absolute ethanol in a 500 ml. standard-taperround-bottom flask equipped with a reflux condenser and a calciumchloride tube. To this, 0.05 mole of'y,'y,'y-trichloro-a-(8-hydroxy-2-quinolyl)-fihydroxypropane dissolvedin 50 ml. of absolute ethanol was added. The mixture was heated verycautiously on a water bath until the violent reaction subsided, then itwas refluxed on a steam bath for five hours. The alcohol was evaporatedon a steam bath at atmospheric pressure and the residue was extractedwith a convenient amount of water. This aqueous extract was filtered toremove the undissolved tarry matter, and the clear filtrate was madefaintly acidic to Congo red paper by the addition of glacial aceticacid. The precipitated heterocyclic acid was collected on a filter andwas recrystallized from ethanol. It had a melting point of 205-206 C.with decomposition.

EXAMPLE IV 8-Alk0xy-2-Quin0line Acrylic Acids A procedure similar to theone used for 8-hydroxy-2- quinoline acrylic acid is employed, exceptthat 0.2 mole of potassium hydroxide was used to convert the 8-loweralkoxy trichloro hydroxypropane intermediates to the correspondingacrylic acids. The methoxy, ethoxy and propoxy derivatives have,respectively melting points of 197l98 C. with decomposition, 2l42l6 C.with decomposition, and 181l82 C.

EXAMPLE V Ethyl Esters of Acids Five thousandths mole of acrylic acidproduct was dissolved in 25 ml. of absolute ethanol in a 250 ml.standardtaper round-bottom flask equipped with :a reflux condenser and acalcium chloride tube, and the solution was saturated with dry hydrogenchloride gas. It was then refluxed on a water bath for two hours. Thesolution was evaporated to dryness on a steam bath, and the gummyresidue was dissolved in a convenient amount of water. This aqueoussolution was neutralized with solid sodium bicarbonate, and it wasextracted with ether. The ether was removed from the extract on a steambath, and the oily residue was crystallized from a hydrocarbon solvent(Skelly B). The ethyl ester of the 8-hydroxy derivative had a M.P. of-86 C., and the ethyl esters of the corresponding methyl, ethyl andpropyl ethers had, respectively, melting points of 5l-52 C., 104-105 C.,and 81-82 C. In a similar manner to that described above the methyl andpropyl esters of the acrylic acid derivatives can be readily prepared byreplacing the absolute ethanol used in Example V with anhydrous methanolor propanol.

In a manner similar to that described in Example I the correspondingalkylaminoalkyl derivatives can be prepared by the use of analkylaminoalkyl chloride in place of ethyl chloride. Usingdiethylaminoethyl chloride and subjecting the resulting ether to thereactions described in Examples II and IV, the8-diethylaminoethoxy2-quinoline acrylic acid is obtained with a meltingpoint of 198- 200 C. with decomposition.

The products of the present invention are characterized by antifungalactivity against dermatophytes such as T. mentagrophytes and E.floccosum. They can be incorporated into conventional inertpharmaceutical carriers including *ointments and powders inconcentrations of 2. 8-hydroxy-2-quinoline acrylic acid. about O.55.0%by weight, in accordance with standard 3. Ethyl (S-hydroxy-Z-quinoline)acrylate. practices in the art, and can be used in this form to inhibitReferences Cited in the file of this patent the growth of dermatophytessuch as noted above in the treatment of athletes foot (tinia pedis) andlike type infec- 5 Chemical Abstracts, P 3197, 21 (1 tions' Chakravartl:J. Sc. Ind. Research (India), 9B, 305-6 I claim: (1950).

1. A compound selected from the group consisting of Matsumul'a et allAmerican Chem- 77, 8-RO-2-quinoline acrylic acid and lower alkyl estersof P the same, where R is selected from the group consisting of 10Valdya at all AIR Pharm- ASSOC Pages hydrogcn and lower alkyl. 13,January (1959).

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 8-RO-2-QUINOLINEACRYLIC ACID AND LOWER ALKYL ESTERS OF THE SAME, WHERE R IS SELECTEDFROM THE GROUP CONSISTING OF HYDROGEN AND LOWER ALKYL.